17A Phase 1, multiple-dose study to evaluate the safety and tolerability of first-in-class XmAb819 (ENPP3 x CD3) in subjects with relapsed or refractory clear cell renal cell carcinoma (ccRCC) (NCT05433)

Abstract Background Despite advances in the treatment of metastatic ccRCC, few patients are cured. Therapies exploiting novel targets are needed. Antigen screening identified ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase family member 3) as having consistent high expression in ccRCC and low expression in normal tissue. ENPP3 is a transmembrane ectoenzyme involved in hydrolysis of extracellular nucleotides. XmAb819 is a 2 + 1 bispecific antibody with high-avidity bivalent ENPP3 binding and mid-affinity monovalent CD3 binding. XmAb819 is engineered for preferential engagement and T cell-mediated cytolysis of high ENPP3-expressing cancer cells. Methods This is a multicenter, open-label, dose-escalation/expansion study enrolling up to 190 participants with advanced ccRCC. The primary objective is safety and tolerability; the secondary objective is preliminary anti-tumor activity. Part A, dose escalation, establishes a priming dose, step-up dose(s), a cohort-limit dose, and the dosing schedule for both intravenous (IV) and subcutaneous (SC) administration. Part B, dose expansion, evaluates the safety and efficacy of the recommended dose established in Part A. All subjects will have disease progression on standard-of-care therapies. XmAb819 will be administered weekly; cohort-limit doses will be administered in 21-day cycles until disease progression or unacceptable toxicity. Adverse events are graded using CTCAE v5.0; CRS using ASTCT Consensus Grading (Lee, 2019). Efficacy is assessed per investigator using RECIST v1.1. Enrollment and dose escalation continues in both the IV and SC cohorts. Significance & Vision XmAb819 is an investigational, novel bispecific T-cell engager engineered to bind and kill high ENPP3-expressing cells. The XmAb819-01 study is a trial designed to enroll patients with ccRCC, a solid tumor that overexpresses ENPP3. Initial evidence of anti-tumor activity in ccRCC has been observed, and tolerability supports continued dose escalation. Trial Schema The dosing period consists of priming, step-up, and target doses.